Candidate Inhibitor of the Volume-Sensitive Kinase Regulating K-Cl Cotransport: The Myosin Light Chain Kinase Inhibitor ML-7 |
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Authors: | SJ Kelley R Thomas PB Dunham |
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Institution: | (1) Department of Biology, Syracuse University, Syracuse, NY 13244, USA, US;(2) Department of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA, US |
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Abstract: | K-Cl cotransport, KCC, is activated by swelling in many cells types, and promotes volume regulation by a KCl efflux osmotically
coupled to water efflux. KCC is probably activated by swelling-inhibition of a kinase, permitting dephosphorylation, and activation
of the cotransporter by a phosphatase. The myosin light chain kinase (MLCK) inhibitor ML-7 inhibits transporters activated
by shrinkage. In red blood cells from three mammalian species, ML-7 stimulated KCC in a volume-dependent manner. Relative
stimulation was greatest in more shrunken cells. Stimulation was reduced by moderate cell swelling and abolished by further
swelling. The half-maximal stimulation is at ∼20 μm ML-7, 50-fold greater than the IC50 for inhibition of MLCK in vitro. Stimulation of KCC by ML-7 did not require cell Ca, while MLCK does. Therefore the target
of ML-7 in stimulating KCC in red cells is probably not MLCK. The evidence favors stimulation of KCC by ML-7 by inhibiting
the volume-sensitive kinase. Qualitatively similar effects of ML-7 on KCC in red cells from three mammalian species suggest
a general mechanism.
Received: 17 March 2000/Revised: 28 July 2000 |
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Keywords: | : K-Cl cotransport — Mammalian red blood cells — ML-7 — Cell volume regulation — Signal transduction |
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